As I have written here previously (for example, "How long does it take the flu to evade a vaccine?"), we have very little data on the evolution of pandemic flu viruses. For instance, we can't make general conclusions about the intervals between pandemics because there just aren't many data points. Moreover, historical pandemic strains are quite different from each other, with some being obviously of avian origin while others arose through recombination or reassortment of avian and mammalian strains. Differences amongst the viruses also obscure the mechanism(s) by which pandemic strains arise.

In the lead for his article, Normile asks, "Is the H5N1 virus now circulating in Asia really the one to watch? How soon will the next pandemic occur? And will it trigger a wave of mortality, as did the 1918 flu, or a just small ripple in the annual influenza death toll?" He quotes well known virologists and evolutionary biologists as doubting whether the presently circulating H5N1 flu bug has the capacity to become a pandemic strain. The article then delves into the role of World War I in generating and spreading the 1918 virus.

Most interesting for me, however, are the straightforward comments concerning how little we know about what is going on:

Although the historical data are interesting, [Mary Lipsitch of Harvard] and others add, they simply aren't conclusive enough to rule an H5N1 pandemic in or out. "We don't know what viruses circulated in the past [among humans], except for the most recent 150 years," says Yoshihiro Kawaoka, a virologist at the University of Tokyo and the University of Wisconsin, Madison. What's more, he says, H5N1 is shattering historical precedents. Never before has a virus so highly lethal for poultry become so widespread and continued in circulation for such a long time. And with the virus continuing to spread, "the risk of mutation is increasing accordingly," says Masato Tashiro, director of WHO's Collaborative Center for Influenza Surveillance and Research at Japan's National Institute of Infectious Diseases in Tokyo. There are so many gaps in what is known about how virulence and pathogenicity evolve, Kawaoka says, that "there is no scientific basis to predict anything."(emphasis added) [The University of Washington's Carl Bergstrom] agrees: "We, as scientists, need to do a good job of something slightly tricky here, which is to convey that our predictions are probabilistic."

Not an easy job, particularly when politicians demand (and promise) unrealistic certainty and the public has an ever poorer understanding of the very nature of science. But because pandemics do historically occur, everyone who knows anything about the flu agrees we need to prepare for the future. The article concludes:

[Paul Offit, of the University of Pennsylvania School of Medicine] hopes the concerns about H5N1 will lead to efforts to strengthen the U.S. infrastructure for vaccine development and production, which he says has deteriorated over the last 50 years. He thinks the message scientists should be sending "is not that we're going to protect you from the bird flu pandemic, but that we're going to be protecting you from a pandemic which may be 20 years from now."

As if that weren't enough to worry about, Oliver Sacks reminds us that the 1918 flu was accompanied by at least one other disease that under other circumstances would have itself been seen as a tragic pandemic. In "Waking to a New Flu Threat" (NY Times, 16 November 05), Sacks and Joel Vilensky note:

The influenza pandemic of 1918 was followed by another epidemic. The disease was encephalitis lethargica, or the "sleepy sickness," and like influenza it spread through most of the world. Its symptoms were extraordinarily varied - most commonly there was lethargy, but sometimes there was insomnia, and even frenzy; sometimes there were paralyses, sometimes mental disorders... In 1982 it was shown that irregularly spaced waves of influenza-pneumonia deaths in Seattle during the early 20th century epidemic were followed approximately one year later by corresponding waves of encephalitis fatalities.

...No cure or causative agent had ever been found and most of the remaining survivors were housed in chronic-care hospitals and forgotten.

...No funds have been allocated to try to better understand this mysterious disease and its relationship to epidemic influenza. Encephalitis lethargica is a particularly insidious disease because it is so variable; any early cases in a new outbreak would almost certainly be misdiagnosed as they were 100 years ago.

It is not unlikely that this disease will return. Perhaps with the imminent influenza epidemic, perhaps not. Regardless, we would do well to re-awaken ourselves to what may be a formidable gathering threat.

Which, as I watch the sun set over Mt. Rainier, Lake Union, and downtown Seattle, will not help me sleep any better tonight.